tbuckley/cabot-search huggingface dataset:
Abstract 2368: Pilot characterization of the salivary microbiome in pediatric cancer patients
Authors: Alejandra Beatriz Cervantes Garduño, Milca de la O García, Jesús Adolfo Yamamoto Nagano, Rocio Del Socorro Cardenas Cardos, Liliana Velasco Hidalgo, Blanca Olivia Almazán García, Gabriela Elisa Mercado Celis
Journal: Cancer Research (2023)

Abstract Microbial populations in the oral cavity have been linked with some malignant diseases, however, the evidence in this regard is poor. Oral microorganisms increase cytokine production and other mediators may be related to carcinogenesis. However, the role of the oral microbiome and its taxonomic composition in pediatric cancer has not been studied. We report a pilot study to assess to compare the microbial diversity of saliva in pediatric patients with cancer and without cancer. Materials and methods: Total saliva samples were collected from 3 cases and 3 controls with cancer, with prior informed consent and assent. Metagenomic sequencing was performed and data was analyzed using CosmosID bioinformatics software. Results: the mean age for the cases is 8.67 years and for the 8-year-old controls, the percentage by sex was 33.3% male and 66.6% female. In the shared analysis of bacterial diversity we found a total of 93 genera, the three genera with the highest abundance in the cases were: Prevotella, Streptococcus and Morococcus. A total of 153 species with differential abundance were identified, in the cases the species with the highest abundance were: Neisseria mucosa, Vellodela dispar, Prevotella melaninogenica and Morococcus cerebrosus. We found differences in bacterial diversity and abundance between cases and controls. The main species that we found in greater abundance in the cases have been related to various processes in the oral cavity, Streptococcus sp increases child caries, Prevotella melaninogenica a broad profile of resistance to families of antibiotics, and Morococcus cerebrosus has been associated with the mineralization of the supragingival dental plaque. Finally Vellodela dispar has been associated with bacteremia in cancer patients. In this pilot study a small number of samples were analyzed, the differences in bacterial diversity should be confirmed by conducting studies with a larger number of samples. Citation Format: Alejandra Beatriz Cervantes Garduño, Milca de la O García, Jesús Adolfo Yamamoto Nagano, Rocio Del Socorro Cardenas Cardos, Liliana Velasco Hidalgo, Blanca Olivia Almazán García, Gabriela Elisa Mercado Celis. Pilot characterization of the salivary microbiome in pediatric cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2368.
Abstract 5101: Inhibition of Notch reverses immunosuppression in basal-like breast cancer
Authors: Qiang Shen, Kiichi Murakami, Pamela Ohashi, Michael Reedijk
Journal: Cancer Research (2023)

Abstract Aberrant Notch activation is a defining feature of basal-like breast cancer (BLBC), which has poor prognosis compared to other breast cancer molecular subtypes. Despite the clinical success of immune checkpoint blockade (ICB) in many malignancies including melanoma and small cell lung cancer, ICB has failed to demonstrate similar response in BLBCs, where most cases are highly infiltrated by tumor-associated macrophages (TAMs). There is increasing evidence that Notch is decisive in regulating intercellular communication in the tumor immune microenvironment (TIME). This includes the recruitment of TAMs which contribute to an immunosuppressive TIME, illuminating the potential of Notch-inhibition as adjuvant immunotherapy in BLBC. To examine the immune phenotype and therapeutic response of BLBC to combined Notch-inhibition and ICB, we employed an in vivo tumorgraft model using murine basal-like mammary tumor 4T1 cells. Briefly, tumor cells were orthotopically injected into the mammary fat pads of BALB/c mice. Using a crossover design, mice were randomly allocated to treatment with either Notch inhibitor (γ-secretase inhibitor, LY411575), anti-PD1 (RMP1-14), or control treatment for 12-days (stage-1), followed by randomization to a second 12-day period (stage 2) with the same, or one of the other treatments. Results: Despite the low response rate of BLBC to ICB alone, Notch inhibition reduced TAMs and induced responsiveness to sequential ICB. This response was characterized by increased cytotoxic T lymphocytes (GrB+, CTL) infiltration of the primary tumor. Similar results were observed when Notch-regulated cytokines (IL-1β and CCL2), crucial to TAM recruitment, were inhibited. Moreover, a more impressive therapeutic effect of sequential treatment was observed in lung metastasis, whereby TAM depletion and increased CTL infiltration were accompanied with near-complete abolition of metastases. Mechanistically, tumor cell Notch signaling upregulates a group of circulating cytokines including IL-1β and CCL2, which prime the lung for metastases. Additionally, compared to primary tumor cells, PD ligand 1 is up-regulated in lung metastases, rendering them profoundly sensitive to sequential ICB treatment. These findings highlight the potential of sequential Notch inhibition and ICB as a novel immunotherapeutic strategy in BLBC. Citation Format: Qiang Shen, Kiichi Murakami, Pamela Ohashi, Michael Reedijk. Inhibition of Notch reverses immunosuppression in basal-like breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5101.
Abstract 1934: Incidence and survival outcomes of younger adults with colorectal cancers by age group: a SEER analysis
Authors: Sheeba Ba Aqeel, Adrienne Groman, Kristopher Attwood, Renuka Iyer, Sarabjit Mukherjee, Deepak Vadehra
Journal: Cancer Research (2023)

Abstract Background: The incidence of colorectal cancer (CRC) is increasing in younger adults (&amp;lt;50 years). Most cases occur between 40 and 49 years. Adolescents and young adults (AYA,15-39 years) with CRC have more aggressive disease. We sought to compare the incidence and outcomes of CRC in AYA with patients in the 40-49 age group. Methods: Surveillance, Epidemiology, and End Result (SEER) was analyzed from 2000-2019. Survival outcomes were analyzed using Kaplan-Meier methods, and comparisons were made using the log-rank test. Cox regression models were used to evaluate univariate and multivariate associations with survival outcomes. SAS v9.4 (Cary, NC) and SEER*Stat v8.4 were used, with a significance level of 0.05.Results: A total of 13,877 AYA patients and 43,771 patients in the age group 40-49 years were identified. The annual incidence rate per 100,000 AYA patients increased from 3.1 in 2000 to 5.3 in 2019. In the 40-49 cohort, the annual incidence rate per 100,000 increased from 21.6 in 2000 to 28.0 in 2019. The annual percent change for incidence for the AYA cohort was higher 3.1% (95% CI 2.8,3.4) than the 40-49 cohort 1.4% (95% CI 1.2,1.6). The 2-year overall survival (OS) rate was not different among the two groups. Disease-specific survival (DSS) was slightly but significantly inferior in the AYA group, 83% (95%CI 0.82,0.83) compared to in the 40-49 cohort, 84% (95%CI 0.83,0.84). Factors associated with inferior DSS in the AYA group were male sex, black race, advanced stage, lack of chemotherapy, and longer time to treatment. Conclusion: Our study shows that the annual percent change in incidence rate was higher in AYA patients compared to those in the 40-49 age group from 2000-2019. DSS was slightly lower in AYA patients; OS was similar in both groups. Further studies are needed to understand the discrepancies. Table 1: Baseline characteristics of AYA and 40-49yr patients AYA 13877(24.1%) 40-49yr 43771(75.9%) Overall 57648(100%) P value Age at diagnosis Mean/Standard deviation 34/4.6 45.5/2.8 42.7/5.9 &amp;lt;0.001 Gender Male 51.9% 53.6% 53.2% &amp;lt;0.001 Race Non-Hispanic White 54.2% 59.4% 58.2% &amp;lt;0.001 Non-Hispanic Black 12.1% 13.3% 13% Asian or Pacific Islander 33% 26.7% 28.2% Unknown 0.6% 0.6% 0.6% Stage Localized 22.2% 26.5% 25.5% &amp;lt;0.001 Regional 31.6% 30.2% 30.6% Distant 20% 19.2% 19.4% Unstaged 1.8% 1.7% 1.7% Blank 24.4% 22.3% 22.8% Chemotherapy No/Unknown 33.8% 39.4% 38.1% &amp;lt;0.001 Citation Format: Sheeba Ba Aqeel, Adrienne Groman, Kristopher Attwood, Renuka Iyer, Sarabjit Mukherjee, Deepak Vadehra. Incidence and survival outcomes of younger adults with colorectal cancers by age group: a SEER analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1934.
Abstract 3515: Histone demethylase KDM5D drives sex-specific differences in colorectal cancer
Authors: Jiexi Li, Zhengdao Lan, Wenting Liao, Jielin Liu, Shan Jiang, Hong Seok Shim, Max Slotnik, Kyle A. LaBella, Wen-Hao Hsu, Xiaoying Shang, Denise Spring, Y Alan Wang, Ronald A. DePinho
Journal: Cancer Research (2023)

Abstract Gender exerts a profound impact on cancer incidence, spectrum and outcomes, yet the molecular genetic bases of such sex differences are ill-defined and presumptively ascribed to X-chromosome genes and sex hormones. Such sex differences are particularly prominent in colorectal cancer (CRC) where men experience higher metastases and mortality. A murine CRC model, engineered with an inducible transgene encoding oncogenic mutant KRASG12D and conditional null alleles of Apc and Trp53 tumor suppressors (designated iKAP), revealed higher metastases and worse outcomes specifically in males with oncogenic mutant KRAS (KRAS*) CRC. Integrated cross-species molecular and transcriptomic analyses identified Y-chromosome gene histone demethylase KDM5D as a transcriptionally up-regulated gene driven by KRAS*-mediated activation of the STAT4 transcription factor. KDM5D-dependent chromatin mark and transcriptome changes showed repression of regulators of epithelial cell tight junction and MHC class I complex components. Deletion of KDM5D in iKAP cancer cells increased tight junction integrity, decreased cell invasiveness, and enhanced cancer cell killing by CD8+ T cells. Conversely, iAP mice engineered with a Kdm5d transgene to provide constitutive KDM5D expression specifically in iAP cancer cells exhibited an increased propensity for more invasive tumors in vivo. Thus, KRAS*-STAT4-mediated upregulation of Y chromosome KDM5D contributes significantly to the sex differences in KRAS* CRC via its disruption of cancer cell adhesion properties and tumor immunity, thus providing an actionable therapeutic strategy for metastasis risk reduction for men afflicted with KRAS* CRC. Citation Format: Jiexi Li, Zhengdao Lan, Wenting Liao, Jielin Liu, Shan Jiang, Hong Seok Shim, Max Slotnik, Kyle A. LaBella, Wen-Hao Hsu, Xiaoying Shang, Denise Spring, Y Alan Wang, Ronald A. DePinho. Histone demethylase KDM5D drives sex-specific differences in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3515.
Abstract 2766: Automation of linear range determination: Enzymatic progress curve applications
Authors: Earl William May, Daniel Urul, Susan Cornell-Kennon, Zhibing Lu, Erik Schaefer, Sam Hoare, France Laliberté, Quay Vong, Paul Payette, Jean Marois
Journal: Cancer Research (2023)

Abstract To characterize modulators of enzymatic activity, a continuous assay format will quantify with confidence the initial reaction velocity far better than an end point assay. When the progress curve is linear from the start and remains linear throughout the experiment, a single end point reading can approximate the reaction rate, but a kinetic assay will provide the rate more accurately. However, if there is a delay in the onset of the reaction, or there are other changes in reaction rate over time, then a single end point reading is insufficient. Thus, important information about the reaction can be missed or mischaracterized. While visual inspection is the most common way to determine the range of the progress curve from which to extract rate information, this method is not practical when thousands of progress curves are generated in an experimental day. We have developed an automated protocol to streamline and optimize the process. The heuristic algorithm analyzes the progress curve to identify different regions for characterization (e.g. lag, primary rate, secondary rate, final plateau) and then extract rates of interest for each of these regions. These rates are subsequently used to measure the specific activity of the enzyme under various assay conditions, and to characterize the modulation of that activity: simple dose-response testing, mode of inhibition analysis, time-dependent inhibition determination, reversibility testing, determination of residence time for reversible inhibitors, and kinact/KI analysis for irreversible inhibitors. We describe the algorithm and several applications as they apply to protein kinases using the PhosphoSens assay platform from AssayQuant within the Analyze module of the Scigilian data analysis package. Citation Format: Earl William May, Daniel Urul, Susan Cornell-Kennon, Zhibing Lu, Erik Schaefer, Sam Hoare, France Laliberté, Quay Vong, Paul Payette, Jean Marois. Automation of linear range determination: Enzymatic progress curve applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2766.
Abstract 3251: The immunostimulatory effect of 9-ING-41, a small molecule GSK-3 inhibitor, in sarcomas
Authors: William J. MacDonald, Samuel Lew, Kelsey E. Huntington, Rishi R. Lulla, Bradley D. DeNardo, Wafik S. El-Deiry
Journal: Cancer Research (2023)

Abstract Due to the rarity and genomic disparity of soft tissue and bone sarcomas, actionable therapeutic targets have been elusive. However, inhibition of GSK-3β has emerged as a potentially promising therapy that could be of great benefit to pediatric and adult sarcoma patients. Saos-2 osteosarcoma and 93T449 liposarcoma cell lines were pretreated at IC5072 with small molecule GSK-3β inhibitor 9-ING-41 (elraglusib). The cells were harvested for western blot analysis after 48 hours of treatment. Additionally, both cancer cell lines as well as TALL-104 T-cells and NK-92 NK cells were treated with 0.5 μM 9-ING-41 for 24 hours and harvested for Luminex cytokine profiling. The western blots demonstrated an increase in cPARP, an apoptotic marker, in both cancer cell lines after 9-ING-41 treatment. Additionally, an increase in PD-L1 expression was observed. The cytokine analysis revealed stimulation of immune cell activity in response to 9-ING-41. Treated T-cells had an increase in CXCL11, which is associated with T-cell recruitment, as well as an increased level of IL-18, which is shown to induce increased IFN-γ in Th1 cells. Additionally, NK-92 cells demonstrated an increase in IL-8 chemokine and an increase in soluble TRAIL (TRAIL/TNFSF10). The cancer cell lines showed a homogenous increase in growth factor TGF-ɑ, however, only the Saos-2 osteosarcoma cell line demonstrated an increase of IL-6. We are further validating the data with follow-up cytokine profiling. The increase in immunostimulatory cytokines as well as the increased expression of PD-L1 suggest a rationale for combining 9-ING-41 with immune checkpoint blockade therapy. The potential synergistic effect of these two therapies is currently under investigation with co-culture experiments of sarcoma and immune cells. The treatment cohorts for these experiments include 9-ING-41 combined with either anti-PD-L1, anti-PD-1, or anti-CTLA-4 immune checkpoint inhibitors. Our results suggest a promising combination therapeutic strategy for patients with soft tissue and bone sarcomas and future work will strive to better elucidate the mechanisms of efficacy. Citation Format: William J. MacDonald, Samuel Lew, Kelsey E. Huntington, Rishi R. Lulla, Bradley D. DeNardo, Wafik S. El-Deiry. The immunostimulatory effect of 9-ING-41, a small molecule GSK-3 inhibitor, in sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3251.
Abstract 287: Novel p62 interaction suggests novel role in glutamate metabolism
Authors: Haley Christine Dahl, Anisha R. Konakalla, Preethi Kanumuri, Basir Mansoor, Anastasia Kelley, Riya Shipurkar, Nikki A. Delk
Journal: Cancer Research (2023)

Abstract Prostate cancer (PCa) is the second most common cause of cancer-related death among American men. Androgen Receptor (AR) transcriptional activity is required for PCa tumor growth. Thus, androgen deprivation therapy (ADT) is a first line PCa therapy. However, 10-20% of patients will inevitably develop lethal castration-resistant PCa (CRPC). Thus, we must uncover the mechanisms that drive CPRC. Chronic inflammation is a known hallmark of cancer initiation and progression. Using the LNCaP human PCa cell line, we have shown that chronic exposure to the inflammatory cytokine, interleukin-1 (IL-1) can transform castration-sensitive PCa cells into castration-resistant PCa cells. IL-1 is elevated in PCa patient tissue and serum and is associated with disease progression and metastasis. IL-1 is clinically relevant, but the role of IL-1 in CRPC development is not fully elucidated. To mimic ADT, we serum-starved LNCaP and the chronic IL-1 sublines, LNas1 and LNbs1, and performed mass spectrometry to identify chronic IL-1-induced changes in protein-protein interactions. Specifically, we looked at p62 protein interactors. p62 is a multi-domain, multifunctional pro-survival protein that mediates autophagic flux in response to cellular stress and serum starvation, promotes NF-κB inflammatory signaling and induces NRF2 antioxidant signaling. We discovered that p62 forms a constitutive interaction with KEAP1 under serum starved and normal growth conditions in the chronic IL-1 sublines. KEAP1 inhibits NRF2 nuclear translocation. In response to antioxidant stress, p62 binds and sequesters KEAP1 from NRF2 to activate NFR2 signaling. Surprisingly, we do not observe constitutive canonical NRF2 signaling in the chronic IL-1 sublines. However, in response to serum starvation, we do see both high basal levels and upregulation, specifically, of the NRF2-induced gene, GCLC. GCLC is a glutamate-cysteine ligase that synthesizes the antioxidant, glutathione. Therefore, using mass spectrometry and immunoprecipitation western blotting, we looked at p62 interactions under serum starvation conditions. While we did not find p62 interaction with GCLC in the chronic IL-1 sublines, we do find that p62 interacts with GLUL. GLUL is a glutamate-ammonia ligase that plays a role in cellular detoxification. These data suggests that chronic IL-1 exposure induces novel p62 interactions that have a role in glutamate metabolism. Citation Format: Haley Christine Dahl, Anisha R. Konakalla, Preethi Kanumuri, Basir Mansoor, Anastasia Kelley, Riya Shipurkar, Nikki A. Delk. Novel p62 interaction suggests novel role in glutamate metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 287.
Abstract 4074: Cellular immunotherapy targeting kappa myeloma antigen for the treatment of multiple myeloma
Authors: Jessica Li, Nicole Haynes, Katherine Cummins, Kavitha Gowrishankar, Kenneth Micklewaithe, Halley Hilton, Rosanne Dunn, Jane Oliaro, Simon Harrison
Journal: Cancer Research (2023)

Abstract Multiple myeloma (MM), the second most common blood cancer, is characterized by the accumulation of malignant plasma cells in the bone marrow. Chimeric Antigen Receptor (CAR)-T cell therapy has recently entered the standard of care for relapsed and refractory MM, following the recent FDA-approval of two CAR-T cell products, ide-cel® and cilta-cel®, which target the B cell maturation antigen (BCMA). However, despite impressive response rates, most patients relapse within 1-3 years. Kappa (κ) myeloma antigen (KMA) is a tumour specific membrane associated protein expressed on malignant plasma cells in patients with kappa light-chain restricted (κ-type) MM. KMA is absent on normal plasma cells and haematopoietic stem cells, making it an attractive and alternative target antigen for CAR-T cell therapy for MM. The monoclonal antibody, KappaMab (MDX-1097), binds to a conformational epitope on KMA, and has been assessed in phase I, IIa and IIb clinical trials in relapse refractory myeloma patients (1). Here, we have engineered a lentiviral vector encoding a second-generation CAR expressing a scFv from MDX-1097, fused to a 4-1BB co-stimulatory domain and CD3 zeta chain. We successfully generated human anti-KMA CAR-T cells with high and stable CAR expression and a predominately memory T cell phenotype. The CAR-T cells selectively killed KMA-expressing tumour lines, secreted interferon-gamma upon target recognition, and demonstrated potent anti-tumour activity in a xenograft model. Anti-KMA CAR-T cell therapy therefore represents a novel and potent treatment ready to enter a phase I clinical trial for patients with myeloma. (1) Spencer et al. Blood Cancer Journal (2019) 9:58 Citation Format: Jessica Li, Nicole Haynes, Katherine Cummins, Kavitha Gowrishankar, Kenneth Micklewaithe, Halley Hilton, Rosanne Dunn, Jane Oliaro, Simon Harrison. Cellular immunotherapy targeting kappa myeloma antigen for the treatment of multiple myeloma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4074.